免疫检查点阻断（ICB）疗法针对程序性死亡1/程序性死亡配体1（PD-1/PD-L1）通路已在治疗广泛癌症中取得了相当大的成功。然而，大多数胰腺癌患者仍然对ICB产生抵抗。此外，预测ICB治疗响应缺乏最佳生物标志物。棕榈酰化由23个硫酰转移酶家族，称为锌指天冬氨酸-组氨酸-组氨酸-半胱氨酸类型棕榈酰转移酶（ZDHHC）介导，这些酶精确控制各种与癌症相关的蛋白质功能，并代表癌症治疗的有前途的药物靶标。在这里，我们发现肿瘤细胞内在的ZDHHC9在胰腺癌组织中过度表达，并与抑制抗肿瘤免疫有关。在同种型胰腺肿瘤模型中，ZDHHC9表达的敲降抑制了肿瘤的进展，并通过修改免疫抑制性（“冷”）到促炎症（“热”）的肿瘤微环境延长了小鼠的生存期。此外，ZDHHC9缺陷主要以CD8+ T细胞依赖性方式增强了抗PD-L1免疫疗法的敏感性。最后，我们使用ZDHHC9-siRNA纳米颗粒系统在胰腺肿瘤中有效地沉默ZDHHC9。总之，我们的研究结果表明，在胰腺肿瘤中，ZDHHC9过度表达是抑制宿主抗肿瘤免疫的一种机制，并强调了失活ZDHHC9作为有效的免疫治疗策略和抗PD-L1疗法的增强剂对抗胰腺癌的重要性。版权所有©2023年作者。由Elsevier Masson SAS出版。保留所有权利。

Immune checkpoint blockade (ICB) therapy targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) axis has achieved considerable success in treating a wide range of cancers. However, most patients with pancreatic cancer remain resistant to ICB. Moreover, there is a lack of optimal biomarkers for the prediction of response to this therapy. Palmitoylation is mediated by a family of 23 S-acyltransferases, termed zinc finger Asp-His-His-Cys-type palmitoyltransferases (ZDHHC), which precisely control various cancer-related protein functions and represent promising drug targets for cancer therapy. Here, we revealed that tumor cell-intrinsic ZDHHC9 was overexpressed in pancreatic cancer tissues and associated with impaired anti-tumor immunity. In syngeneic pancreatic tumor models, the knockdown of ZDHHC9 expression suppressed tumor progression and prolonged survival time of mice by modifying the immunosuppressive ('cold') to proinflammatory ('hot') tumor microenvironment. Furthermore, ZDHHC9 deficiency sensitized anti-PD-L1 immunotherapy mainly in a CD8+ T cell dependent manner. Lastly, we employed the ZDHHC9-siRNA nanoparticle system to efficiently silence ZDHHC9 in pancreatic tumors. Collectively, our findings indicate that ZDHHC9 overexpression in pancreatic tumors is a mechanism involved in the inhibition of host anti-tumor immunity and highlight the importance of inactivating ZDHHC9 as an effective immunotherapeutic strategy and booster for anti-PD-L1 therapy against pancreatic cancer.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.